Depression is a serious illness associated with a high morbidity resulting from physical disorders and an increased mortality resulting from accidents and suicide. Major depression recurs in about half the patients diagnosed with depression. Major depression is characterized by feelings of intense sadness and despair, mental slowing and loss of concentration, pessimistic worry, agitation, and self-deprecation. Physical changes also occur, especially in severe or “melancholic” depression. These include insomnia or hypersomnia, anorexia and weight loss (or sometimes overeating), decreased energy and libido, and disruption of normal circadian rhythms of activity, body temperature, and many endocrine functions.
Treatment regimens commonly include the use of tricyclic antidepressants, monoamine oxidase inhibitors, some psychotropic drugs, lithium carbonate, and electroconvulsive therapy (ECT) (see, for example, R. J. Baldessarini in Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th Edition, Chapter 19, McGraw-Hill, 1996 for a review). More recently, new classes of antidepressant drugs are being developed including selective serotonin reuptake inhibitors (SSRIs), specific monoamine reuptake inhibitors and 5-HTIA receptor agonists, antagonists and partial agonists.
Thus, depressed patients may be treated with antidepressants continuously for years. There are, however, important drawbacks to the use of available drugs. Twenty-five % to thirty-five % of patients show only minimal improvement, and side effects and toxicity can occur. By way of example, tricyclic antidepressants (TCAs) are especially bothersome in elderly patients, with postural hypotension being a particularly severe problem and selective serotonin reuptake inhibitors (SSRIs) may induce nausea, vomiting, diarrhea, headache and sexual dysfunctions. Severe drug interactions can also result from the co-administration of monoamine oxidase inhibitors and either TCAs or SSRIs.
As a consequence, there is a need for antidepressant drugs that would be active at doses intended to be as low as possible in order to minimize the risk of side effects and drug interactions, especially in elderly patients, often exposed to several drugs concurrently.
Anxiety is an emotional condition characterized by feelings such as apprehension and fear accompanied by physical symptoms such as tachycardia, increased respiration, sweating and tremor. It is a normal emotion but when it is severe and disabling it becomes pathological. Anxiety-related impairments are frequent medical conditions, and include generalized anxiety disorders (GAD), panic anxiety, posttraumatic stress disorder, phobias, anxious depression, anxiety associated with schizophrenia, restlessness and general excitation states.
The main anxiolytic drugs used at present are benzodiazepines. Potent benzodiazepines are effective in panic disorder as well as in generalized anxiety disorder (GAD). In addition to their tranquillizing action, benzodiazepines also exert a variety of unwanted side effects, including sedative, anterograde amnesia and ethanol potentiation. However, the major factor limiting the therapeutic use of benzodiazepines are sequelae following their chronic use, in particular dependence liability. For a general review of benzodiazepines and their use in the treatment of anxiety-related disorders, see, for example, Schader and Greenblatt, 1993, N. Engl. J. Med. 328 (19): 1398-1405; and R. J. Baldessarini in Goodman & Gilman's Tite Pharmacological Basis of Therapeutics, 9th Edition, Chapter 18, McGraw-Hill, 1996.
Thus, there is a need for agents useful in treating the symptoms of anxiety-related disorders without, or with a decreased severity of, side effects, such as dependence liability and sedation. There is also a need for agents useful in the treatment of emotional, behavioural, neurological, and mental disorders, collectively referred to herein as “affective” all of which include anxiety and/or depression as a symptom.
Cognitive brain disorders are characterized clinically by progressive loss of memory, cognition, reasoning, executive functioning, planning, judgment and emotional stability, gradually leading to profound mental deterioration. A wide range of disorders can lead to disturbances of cognition. In particular, the increase of medical screening for dementia, has led to an increasing number of patients which are being identified who do not meet the diagnostic criteria for dementia but nonetheless have significant memory or cognitive impairment, defined as Mild Cognitive Impairment.
Mild Cognitive Impairment (MCI) is a condition characterized by mild recent memory loss without dementia or significant impairment of other cognitive functions to an extent that is beyond that expected for age or educational background. Criteria for diagnosis of MCI are: memory complaint; abnormal activities of daily living; abnormal general cognitive functioning; abnormal memory for age; not demented.
The number of patients falling in the categories of MCI, Age-Associated Memory Impairment, Age-Related Cognitive Decline or similar diagnostic categories is staggering. For example, according to the estimates of Barker et al. Br J Psychiatry, 1995 No 167(5):642-8, there are more than 16 million people with Age Associated Memory Impairment in the U.S. alone. An advisory panel to the US Food and Drug Administration ruled on Mar. 13, 2001, that MCI, “a condition separate from dementia in Alzheimer's Disease (AD),” is a valid target for new drug therapies, regardless of whether a particular drug also slows the progression to dementia. Only a few drugs are commercially available to improve cognitive function. Current therapies can cause unpleasant side-effects and lead to difficulties in maintaining patient compliance. In particular in some neuropsychological disease states, some interventions, often worsen cognitive functions. Thus, the need of new drugs that ameliorate cognition without worsening other side effects, is very high.
A variety of medications (including nonsteroidal anti-inflammatory drugs) hormones (especially estrogen), vitamins (such as, for example, vitamin E) and herbal preparations (especially Gingko biloba) have been advocated as treatments for cognitive impairment. Acetylcholinesterase inhibitors, labelled for use in Alzheimer's disease, are also being tested for MCI. Examples of acetylcholinesterase inhibitors tested for the treatment of MCI include but are not limited to Donepezil hydrochloride, or Aricept® described in U.S. Pat. No. 4,895,841, WO2001/066114 and EP1311272B1. While some of these agents hold promise, robust effects from carefully executed, well-controlled clinical trials are still nonexistent. For all these reasons the unmet medical need in cognitive impairment and, in particular, MCI, is still very high.
More recently, the sigma receptors have emerged as possible therapeutic targets for various diseases such neuropsychiatric disorders and cancer (Casellas et al., 2004; Hayashi and Su, 2004). The sigma receptors are widely distributed in the mammalian brain; and these receptors recognize a diverse array of centrally acting substances including opiates, antipsychotics, antidepressants, phencyclidine (PCP)-related compounds, and neurosteroids (Walker et al., 1990; Bowen, 2000). Moreover, the observation that several sigma receptor ligands are neuroprotective in both in vivo and in vitro models of ischemia has generated great interest in targeting these receptors to enhance neuronal survival following stroke (Takahashi et al., 1996; Lockhart et al., 1995). Dysregulation of intracellular calcium homeostasis greatly contributes to the demise of neurons following an ischemic insult in the central nervous system. The sigma receptors have also been implicated in numerous physiological and pathophysiological processes such as learning and memory (Senda et al., 1996; Hiramatsu et al., 2006), movement disorders (Matsumoto et al., 1990), and drug addiction (McCracken et al., 1999).
So far, two sigma receptor subtypes have been identified on the basis of their pharmacological profile. Only the sigma-1 receptor has been cloned (Hanner et al., 1996). However, the sigma-2 receptor has been shown to be a separate molecular entity (Langa et al., 2003). The sigma-1 receptor has high affinity for positive isomer of bezomorphas such as (+)-pentazocine and (+)-SKF-10,047 while the sigma-2 receptor has a high affinity for ibogaine (Vilner and Bowen, 2000). In particular, sigma 1 receptor agonists have also been shown to have antidepressant effects. In this regard, Sigma 1 receptor ligands show clear antidepressant effects in several animal models. By way of example, the selective sigma 1 receptor agonists (+)-pentazocine, (+)-SKF-10,047, igmesine, OPC14523, DTG or SA4503 reduce the immobility time in the forced swim test or are active in the tail suspension test (Ukai et al. 1998, Matsuno et al., 1996, Tottori et al. 1997, Kinsora et al. 1998). U.S. Pat. No. 5,034,419 describes N-cycloalkylalkylamines, which are also sigma 1 receptor agonist.
The function and mechanism of action of the sigma receptors is not well understood. Accordingly, studies of sigma receptor modulation of biological processes have resulted in considerable controversy in the literature. There are conflicting reports as to whether sigma receptor ligands, such as sigma 1 receptor agonists/antagonists, exert their effects via actions on sigma receptors (Hayashi et al., 1995; Monnet et al., 2003) or non-specific interaction with other targets, in particular, NMDA receptors (Nishikawa et al., 2000; Kume et al., 2002). To some extent, analysis and interpretation of the results has been confounded by limitations in the pharmacological approaches used. For example, sigma receptors and NMDA receptors both bind PCP and related compounds (eg. MK-801) with high affinity (Sircar et al., 1987), and thus, such drugs cannot be used to discriminate between direct and indirect effects. Also, previous studies have not effectively used specific sigma receptor antagonists to confirm results.
Captodiamine (Covatine) has been known as an anxiolytic agent for several decades. Azoulay, Le Bezu and Leyritz (Ann. Med. Psychol. (Paris), 1956 December 114 (5); 856-861 reported a study on the treatment with Covatine of “depressive states” resistant to largactil. Covatine was found to be useful in only one patient (observation 1), a patient in a depressive state with suicidal ideation who was subsequently diagnosed to have a major anxiety behavior and to be “depressed”. The most appropriate interpretation of the terms “depressed” and “depressive state” used in this paper is in relation to an emotional and/or deflated state. In 1956, depression and schizophrenia were classified as psychotic states and anxiety, along with “depressive reactions”, were referred to as neuroses (Bowman and Rand, 1980). This is consistent with the diagnosis of the patent Observation 1 as being a case of neurosis. Secondly, the effects of Covatine in this study were concluded to be ineffective in the treatment of individuals with psychosis (Grebe, 1959).
From the discussion above, it is clear that the treatment of: (a) symptoms of anxiety and/or depression associated with an “affective” disorder; and/or (b) symptoms associated with a cognitive impairment disorder is still an area of high unmet medical need with no effective drugs. Despite intensive research into the mechanism of the pathogenesis of these diseases and the development of new drugs for effective treatment of this disease, there also remains a significant interest in and need for additional or alternative therapies for treating, preventing and/or delaying the onset and/or development of symptoms associated with cognitive impairment disorders, and/or symptoms of anxiety and/or depression associated with “affective” disorders. The moderate and inconsistent effect observed with some drugs leave space to identify more effective and safe treatments. In particular, there is a need for additional or alternative therapies which have efficacy in managing the core symptoms associated with cognitive impairment disorders, and/or symptoms of anxiety and/or depression associated with “affective” disorders. In particular, there is a need for new therapeutic agents which can improve the quality of life for patients with symptoms associated with these disorders.